Quantification of bone metabolic activity in the natural course of fractural lesions measured by quantitative SPECT/CT

Objective(s): While increased uptake at the bone fractural site gradually decreases over time on bone scans, the rate of change has not been quantitatively evaluated. The purpose of this study was to quantify the extent of bone metabolic changes in fractural lesions on bone SPECT/CT. Methods: We reviewed bone scans acquired by dedicated SPECT/CT and chose those scans in which quantitative SPECT/CT of the same range was acquired twice or more. We set the region of interest on lesions of bone fracture and degeneration, and measured the maximum standardized uptake value (SUVmax). From the SUVmax of lesions and the interval between scans, a value for 30-day change in SUVmax was calculated as ∆SUVmax30d. The relationship between preSUVmax, SUVmax for the first scan of the comparison, and ∆SUVmax30d was evaluated utilizing a linear least-squares method. Furthermore, we assessed the ability to differentiate between fracture and degeneration using receiver operating characteristics (ROC) analysis and the Mann-Whitney U test. All cases were then categorized into five groups according to preSUVmax. Values of p <0.05 were considered statistically significant. Results: We investigated 175 scans from 60 patients and analyzed scan combinations for 157 fractural lesions and 266 degenerative lesions. The relationship between preSUVmax of fractural lesions and ∆SUVmax30d was approximated as ∆SUVmax30d =-0.15×preSUVmax +1.35 (R2=0.60, p<0.0001). Area under the curves for all cases, 30≤ preSUVmax, 20≤ preSUVmax <30, 15≤ preSUVmax <20, 10≤ preSUVmax <15, and preSUVmax <10 were 0.73, 0.89, 0.86, 0.80, 0.91, and 0.59, respectively. Median ∆SUVmax30d was significantly lower at fractural lesions than at degenerative lesions (-0.62 vs -0.04; p <0.0001). As for analyses of groups divided by preSUVmax, all median ∆SUVmax30d for fractural lesions were significantly lower than those of degenerative lesions except for the group with preSUVmax <10. Conclusion: The increased uptake at the fractural bone lesion observed in the quantitative bone SPECT/CT gradually decreased at the rate of SUV 0.15 per month, which showed a different trend with degenerative change.


Introduction
Bone scans show increased tracer uptake in fractural lesions. When evaluating bone metastasis, uptake in the fracture occasionally interrupts precise diagnosis, especially for solitary lesions (1). Accumulation at fractural sites is well known to gradually decrease (2), Asia Ocean J Nucl Med Biol. 2023; 11 (1): 30-36 31 and this decline can be one of the keys to differentiating fractural lesions from malignant lesions. However, how fast the accumulation decreases over time has not been characterized objectively. Recent advances in single photon emission computed tomography (SPECT) have been improving quantitative technology (3,4). In addition to software-based methods (5), hardware-based techniques combined with computed tomography (CT) can accurately calculate quantitative values (6). Standardized uptake value (SUV), a representative quantitative value used initially in positron emission tomography (PET), has also been used in SPECT quantification. Using SUV calculated from quantitative SPECT/CT systems, we can discriminate bone metastases from benign lesions (7). In addition, SUV from bone SPECT can be used to diagnose various benign diseases (8,9) and evaluate physiological bone metabolism (10) as well as monitor the effects of treatment in cancer therapy (11).
Clarification of quantitative changes in the bone metabolism of fractural lesions is essential to understand the pathogenesis of bone metabolism. The changes observed in fractures are expected to differ from those involved in degenerative lesions, which also often show positive accumulation on bone scans. The purpose of this study was therefore to describe the extent of bone metabolic changes in fractural lesions observed by bone scintigraphy.

Patients
The protocol for this retrospective study was approved by the institutional review board of Saitama Medical University International Medical Center (approval no. #20-056), and the need for written informed consent was waived. We reviewed all clinical images from bone scans acquired between August 2017 and April 2020 from a dedicated SPECT/CT platform (Symbia Intevo; Siemens, Erlangen, Germany). We included only those cases in which quantitative SPECT/CT of the same range was acquired at least twice. Among those, we excluded scans showing extravascular tracer leakage or insufficient image quality for the calculation of quantitative values. We also eliminated from analysis those scans showing no apparent fracture or degeneration. In addition, while we used two kinds of tracers for bone scans, scans that used different tracers were also avoided in the analysis.

Image analysis
Two board-certified nuclear medicine physicians evaluated lesions showing increased uptake on SPECT images and chose those lesions considered to represent either fracture or degeneration by consensus. The physicians drew regions of interest (ROIs) on a workstation for nuclear medicine (syngo.via NM Oncology WF for VA 30; Siemens), and SUV was calculated by the following equation: In the analysis, SUVmax was used offering maximal SUV from the pixels within the ROI. The ROI was manually drawn on follow-up images in the same area as in the first scan, and SUVmax was measured.

Statistical analysis
For a bone scan image in which a fractural or degenerative lesion was present, we examined all other follow-up scans in which the same lesion was observable and recorded the SUVmax of each lesion and the interval in days between scans. If scans were performed three times or more, data were recorded between all combinations, i.e., when three scans were performed, data were recorded three times; between the first and second scans, between the first and third scans, and between the second and third scans. In cases where abnormal uptake disappeared during follow-up, we did not include the case in subsequent analyses.
To facilitate an understanding of the rate of change, standardized values for the 30-day rate of change where postSUVmax and preSUVmax indicate SUVmax at the later and earlier scans, respectively. We evaluated how much SUVmax of the day changed after 30 days utilizing a linear leastsquares method on fractural and degenerative lesions by comparing the relationship between preSUVmax and SUVmax30d. In addition, we evaluated the ability to differentiate between fracture and degeneration by receiver operating characteristics (ROC) analysis and the Mann-Whitney U test. Areas under the curve (AUCs) were calculated for ROC analysis. These differential abilities were analyzed in all cases and the following five groups for preSUVmax were defined: 30≤ preSUVmax, 20≤ preSUVmax <30, 15≤ preSUVmax <20, 10≤ preSUVmax <15, and preSUVmax <10. Values of p <0.05 were considered statistically significant. We used integrated statistical software (Prism 8.4.3; GraphPad Software, San Diego, CA, USA).

Patients and analyzed lesions
Among patients who underwent bone SPECT/CT scan twice or more, we reviewed 666 bone SPECT/CT scans from 206 patients. A total of 19 scans met the exclusion criteria, comprising 18 scans with extravascular leakage of tracer and 1 scan with insufficient image quality. We also excluded a further eight scans in which paired scans were unavailable. Moreover, we excluded 464 cases in which no fracture or degeneration lesions were evident. As a result, we finally included and analyzed 175 scans from 60 patients in this study. Table  1 summarizes detailed patients characteristics. Among these, we identified 157 combinations for fractural lesions and 266 combinations for degenerative lesions. Table 2 summarizes the detailed characteristics of these combinations. None of these combinations of scans used different tracers. Figure 1 shows representative cases.  With this formula, the 95%CI of the slope was -0.17 to -0.13, and the intercept ranged from 0.97 to 1.73. The R 2 value was 0.60, and the pvalue was <0.0001. This indicated that the fractural lesion that showed an initial SUV of 40 displayed a decrease in SUV of 4.6 per 30 days, SUV=30 decreased by 3.1 per month, and SUV=20 decreased by 1.6 per month.
With this formula, the 95%CI of the slope was -0.06 to -0.03, and the intercept ranged from 0.33 to 0.92. The R 2 value was 0.09, and the pvalue was <0.0001.  Figure 3 illustrates the ROC curves to differentiate fractural lesions from degeneration. Table 3 summarizes the AUC of the ROC and other statistical data for differentiating fractures from degeneration in all cases and in the five groups divided according to preSUVmax.

Figure3.
Receiver operating characteristic analyses to discriminate fracture from degeneration by SUVmax30d. Diagonal red dotted lines represent non-discriminatory tests Table 3. Summary of statistical data on differential ability by preSUVmax

Discussion
Utilizing quantitative SPECT/CT, we evaluated the natural course of bone metabolic activity in fractural and degenerative lesions using SUVmax. We found that the SUVmax of fracture decreased significantly earlier than that of degeneration, which may offer a key characteristic for discriminating between these pathologies. The significance of the present study is that we quantitatively demonstrated the possibility of determining whether a lesion showing increased uptake represents fracture after a certain period when encountering such cases.
The uptake on fractural lesions gradually decreased at a constant rate, whereas degenerative lesions appeared to show relatively little change. Although not included in this study, malignant bone tumors, including metastases, without any treatment are expected to increase the uptake in a short period, further facilitating discrimination between them. We evaluated the rate in SUVmax over time and standardized the changes to 30 days as SUVmax30d. The SUVmax30d was significantly higher for fractural lesions than for degeneration, and these findings were consistently observed in groups with 10≤ SUVmax. While no significant difference between values was identified for the group with SUVmax <10, such SUVs can be considered to reflect physiological or near-physiological uptake.
Inverting the approximate equation in fractural lesions, the SUVmax30d was estimated as around zero when preSUVmax was 9. A previous paper reported that the SUVmax of normal bone is approximately 5-10 (12-14), generally consistent with our findings. We can find a lot of positive numbers of SUVmax30d in Figure 2, which indicates uptake increase after follow-up, in fractures and degeneration in which SUVmax was around 10 or less. Such results may indicate that SUVmax30d is converging to zero. On the other hand, some combinations take an extremely high positive SUVmax30d among them. Such values may suggest that a fractural site has re-fractured and is showing even more increased accumulation. Once fractured, these fragile areas could be refractured by minor stressors such as coughing or trauma (15).
Detailed interviews with the patients are indispensable to understand the pathological condition. There seem to be more certain technical errors in the quantification of SPECT/CT than in PET, but these errors are generally considered within the permissible range (16). Moreover, Arvola et al. reported that SUVs of SPECT/CT and PET/CT with 18 F-NaF are quite similar (12). We used 30 days for standardization because this is easy to understand as a quantitative value, but we should note that this study did not evaluate actual data from a 30-day period for reference. A more extended period may be required to assess changes, or determination over a shorter period may be feasible. Additional prospective studies are necessary to clarify the optimal timings in the future. We consider the present study had some limitations. First, final diagnoses were not based on pathological results, but rather on visual diagnoses by expert nuclear medicine physicians. Decisions in the present study could thus have included some misdiagnosed pathologies. Second, this study did not include any malignant bone lesions. Differentiating bone metastasis from benign fracture is clinically essential, but adding metastatic lesions into this kind of analysis would not be easy, because such metastatic lesions should be treated immediately. Modification of the uptake by treatment cannot be excluded in this analysis. Third, some of the combinations included relatively long periods between scans.
After a certain point, uptake stops changing, which would introduce errors into the calculation. In this study, the maximum interval between scans was 886 days, and we cannot exclude the possibility of underestimating the change in such cases. And finally, we evaluated several types of fractures together. The healing process of a fracture includes an inflammatory phase, a reparative phase, and a remodeling phase (17), and the tracer accumulation of bone scintigraphy varies according to these phases.
Therefore, it is important to evaluate separately by the exact injury time and the type of fracture or location.

Conclusion
Quantitative SPECT/CT depicted the natural time course of bone metabolic activity on fracture and degeneration by SUVmax.
SUVmax decreased significantly earlier for fracture than for degeneration.